J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Original Article

Volume 12, Number 11, November 2020, pages 711-723

Thyroid-Stimulating Hormone Receptor Autoimmunity and Local Factors in Multiple Risk Factors Are Mainly Involved in the Occurrence of Pretibial Myxedema

Figure 3. Serum TRAb levels in PTM patients higher than Graves’ disease without PTM (GD w/o PTM) patients and normal persons. Comparison of serum TRAb levels was performed between 400 PTM cases and 800 control cases. The control cases included 400 GD w/o PTM cases and 400 normal person cases. Serum TRAb levels (129.151 ± 165.948 IU/L) in PTM group were significantly higher than those (11.163 ± 10.815 IU/L) in GD w/o PTM patients and those (0.383 ± 0.198 IU/L) in normal persons (P < 0.001). The serum TRAb levels (11.163 ± 10.815 IU/L) in GD w/o PTM cases were significantly higher than those (0.383 ± 0.198 IU/L) in normal persons (P < 0.01). PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.

Figure 4. Positive correlation between serum TRAb levels and PTM severity. (a) Six variants of PTM lesions consisted of nodular (Nod), tumorous (Tum), plaque-like (Pla), mixture (Mix), diffuse (Dif), and elephantiasic (Ele) variants. The volume of nodule variant was the smallest, and the elephantiasic variant was the largest. (b) Serum TRAb levels in six PTM variants were positively correlated with the severity of PTM lesions. Serum TRAb levels were the lowest (61.52 ± 96.93 IU/L) in the nodular variant and the highest (225.5 ± 280.9 IU/L) in the elephantiasic variant (P < 0.001). The serum TRAb levels gradually increased with the volume increase of PTM lesions (r = 0.81, P < 0.01). PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.

Figure 5. Significant improvement of PTM with multipoint intralesional injection glucocorticoid treatment. In 371 glucocorticoid therapy cases, the injection frequency in the nodule, plaque, diffuse swelling and mixed variants was once a week. The treatment of elephantiasic variant was divided into three stages in 1.5 to 2 years. The first stage was once a week for two to three treatment sessions, once a month in the second stage for 6 months, and once every 3 months in the third stage for 6 months. The tumor variant was treated with surgery + subdermal injection of glucocorticoid at surgical sites. Finally, 330 cases achieved complete response and 41 cases achieved major response. The cases with complete response included nodule (61 cases), plaque (99 cases), diffuse swelling (124 cases), mixed (16 cases), tumor (11 cases) and elephantiasis (19 cases). (a, c, e and g) PTM variants before glucocorticoid therapy. (b, d, f, and h) Complete response of PTM variants after glucocorticoid therapy. Forty-one cases with major response included plaque (13 cases), diffuse swelling (21 cases) and elephantiasis (seven cases). (i, k) Elephantiasis with polypoid and elephantiasis with fungating appearance before glucocorticoid therapy, respectively. (j, l) The major response after glucocorticoid therapy. PTM: pretibial myxedema.

Figure 6. PTM remission related to decrease of serum TRAb levels with glucocorticoid treatment. In 330 cases with complete response, serum TRAb levels (56.45 ± 79.21 IU/mL) after therapy decreased by 84.40 ± 123.48 IU/L compared with those (130.80 ± 165.61 IU/mL) before therapy (paired t = 9.422, P < 0.001). Serum TRAb values of six PTM variants after therapy decreased by 35.57 ± 86.80 IU/L (nodule, 61), 79.27 ± 123.54 IU/L (plaque, 99), 81.28 ± 130.07 IU/L (diffuse swelling, 124), 70.33 ± 61.05 IU/L (mixed, 16), 69.60 ± 68.68 IU/L (tumor, 11), and 140.97 ± 130.72 IU/L (elephantiasis, 19), respectively (paired sample t test, P < 0.001). In 62 cases with repeated (two to four) relapses, serum TRAb levels decreased by 128.57 ± 172.48 IU/L from 187.49 ± 203.78 IU/L before the first treatment session to 58.93 ± 93.96 IU/L after the final treatment session when they achieved complete response. PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.

Figure 7. PTM relapses related to increase of serum TRAb levels after stopping glucocorticoid treatment. In 330 cases with complete response, serum TRAb levels (59.85 ± 81.12 IU/L) in relapse cases were higher than those (30.44 ± 62.10 IU/L) in non-relapse cases (n = 330, t = 2.14, P = 0.033). In 165 relapse cases, serum TRAb levels increased by 51.18 ± 115.99 IU/L from complete lesion regression (TRAb, 59.23 ± 70.06 IU/L) after therapy to the first relapse (TRAb, 110.41 ± 123.78 IU/L) (n = 165, paired t = -3.796, P < 0.001). PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.

**Table 1.** The Distribution and Comparison of 19 Factors Among Three Groups
Factors and its reference range	Case-control groups	χ²/t^a	P1	χ²/t^b	P2	χ²/t^c	P3
^aχ²/t: PTM vs. normal persons. ^bχ²/t PTM vs. GD w/o PTM. ^cχ²/t: PTM vs. control. ^dP > 0.05, no difference; 0.01 < P < 0.05, difference; *P < 0.01, significant difference. PTM: pretibial myxedema; GD: Graves’ disease; GD w/o PTM: GD without PTM; AITD: autoimmune thyroid disease; TSH: thyroid-stimulating hormone; TT3: total T3; FT3: free T3; TT4: total T4; FT4: free T4; TRAb: TSH receptor autoantibody; TPOAb: thyroid peroxidase autoantibody; TgAb: thyroglobulin autoantibody.
Gender				0.500	^d	63.726	**	24.552	**
Male	210 (52.5%)	200 (50.0%)	100 (25.0%)
Female	190 (47.5%)	200 (50.0%)	300 (75.0%)
Age	45.73 ± 12.183	39.72 ± 22.547	37.97 ± 15.503	4.694	**	7.874	**	7.519	**
Range (min - max) year	16 - 86	1 - 80	1 - 80
Occupation				0.343	^d	0.009	^d	0.154	^d
Unemployed	110 (27.5%)	106 (26.5%)	112 (28.0%)
Worker	71 (17.8%)	71 (17.8%)	72 (18.0%)
Peasant	146 (36.5%)	140 (35.0%)	135 (33.8%)
Office staff	73 (18.3%)	83 (20.8%)	81 (20.3%)
Cigarette smoking	147 (36.8%)	71 (17.75%)	140 (35.0%)	36.420	**	0.266	^d	13.712	**
Alcohol drinking	136 (34.0%)	172 (43.0%)	112 (28%)	6.842	**	3.366	^d	0.264	^d
Local skin trauma	94 (23.5%)	19 (4.8%)	25 (6.3%)	57.967	**	47.000	**	151.676	**
Venous stasis posture	286 (71.5%)	133 (33.3%)	140 (35.0%)	117.31	**	107.032	**	149.701	**
AITD history/AITD	395 (98.8%)	6 (1.5%)	400 (100.0%)	756.61	**	5.031	^d	276.827	**
Exophthalmos	286 (71.5%)	0	234 (58.5%)	445.14	**	14.857	**	193.853	**
Acropachy	57 (14.3%)	0	37 (9.3%)	61.373	**	4.822	*	34.218	**
I-131 treatment	269 (67.3%)	0	245 (61.3%)	405.27	**	3.135	^d	146.083	**
TT3 (0.92 - 2.79 nmol/L)	2.02 ± 1.75	1.54 ± 0.36	2.39 ± 2.19	4.815	**	-2.514	*	0.498	^d
FT3 (3.54 - 6.47 pmol/L)	6.08 ± 4.31	4.77 ± 0.67	7.15 ± 6.22	5.969	**	-2.805	**	0.448	^d
TT4 (58.10 - 140.60 nmol/L)	110.58 ± 60.97	96.75 ± 17.64	114.22 ± 67.23	3.930	**	-0.760	^d	1.447	^d
FT4 (11.48 - 23.22 pmol/L)	19.63 ± 14.33	16.23 ± 2.11	21.36 ± 18.83	4.659	**	-1.460	^d	0.976	^d
TSH (0.55 - 4.78 mIU/L)	10.957 ± 25.988	2.174 ± 1.040	9.099 ± 22.333	6.625	**	0.995	^d	3.637	**
TRAb (0.00 - 1.75 IU/L)	129.15 ± 165.95	0.38 ± 0.20	11.16 ± 10.82	15.519	**	14.190	**	14.858	**
TPOAb (0.00 - 34.00 IU/mL)	243.96 ± 273.46	13.32 ± 6.30	227.71 ± 208.57	16.715	**	0.942	^d	8.107	**
TgAb (0.00 - 115.00 IU/mL)	499.20 ± 1091.53	20.96 ± 44.62	658.01 ± 1,172.04	8.679	**	-1.974	*	-2.701	**

Table 1. The Distribution and Comparison of 19 Factors Among Three Groups

Factors and its reference range

Case-control groups

χ²/t^a

χ²/t^b

χ²/t^c

PTM (n = 400)

Normal persons (n = 400)

GD w/o PTM (n = 400)

^aχ²/t: PTM vs. normal persons. ^bχ²/t PTM vs. GD w/o PTM. ^cχ²/t: PTM vs. control. ^dP > 0.05, no difference; *0.01 < P < 0.05, difference; **P < 0.01, significant difference. PTM: pretibial myxedema; GD: Graves’ disease; GD w/o PTM: GD without PTM; AITD: autoimmune thyroid disease; TSH: thyroid-stimulating hormone; TT3: total T3; FT3: free T3; TT4: total T4; FT4: free T4; TRAb: TSH receptor autoantibody; TPOAb: thyroid peroxidase autoantibody; TgAb: thyroglobulin autoantibody.

Gender

0.500

63.726

24.552

Male

210 (52.5%)

200 (50.0%)

100 (25.0%)

Female

190 (47.5%)

200 (50.0%)

300 (75.0%)

Age

45.73 ± 12.183

39.72 ± 22.547

37.97 ± 15.503

4.694

7.874

7.519

Range (min - max) year

16 - 86

1 - 80

Occupation

0.343

0.009

0.154

Unemployed

110 (27.5%)

106 (26.5%)

112 (28.0%)

Worker

71 (17.8%)

72 (18.0%)

Peasant

146 (36.5%)

140 (35.0%)

135 (33.8%)

Office staff

73 (18.3%)

83 (20.8%)

81 (20.3%)

Cigarette smoking

147 (36.8%)

71 (17.75%)

140 (35.0%)

36.420

0.266

13.712

Alcohol drinking

136 (34.0%)

172 (43.0%)

112 (28%)

6.842

3.366

0.264

Local skin trauma

94 (23.5%)

19 (4.8%)

25 (6.3%)

57.967

47.000

151.676

Venous stasis posture

286 (71.5%)

133 (33.3%)

140 (35.0%)

117.31

107.032

149.701

AITD history/AITD

395 (98.8%)

6 (1.5%)

400 (100.0%)

756.61

5.031

276.827

Exophthalmos

286 (71.5%)

234 (58.5%)

445.14

14.857

193.853

Acropachy

57 (14.3%)

37 (9.3%)

61.373

4.822

34.218

I-131 treatment

269 (67.3%)

245 (61.3%)

405.27

3.135

146.083

TT3 (0.92 - 2.79 nmol/L)

2.02 ± 1.75

1.54 ± 0.36

2.39 ± 2.19

4.815

-2.514

0.498

FT3 (3.54 - 6.47 pmol/L)

6.08 ± 4.31

4.77 ± 0.67

7.15 ± 6.22

5.969

-2.805

0.448

TT4 (58.10 - 140.60 nmol/L)

110.58 ± 60.97

96.75 ± 17.64

114.22 ± 67.23

3.930

-0.760

1.447

FT4 (11.48 - 23.22 pmol/L)

19.63 ± 14.33

16.23 ± 2.11

21.36 ± 18.83

4.659

-1.460

0.976

TSH (0.55 - 4.78 mIU/L)

10.957 ± 25.988

2.174 ± 1.040

9.099 ± 22.333

6.625

0.995

3.637

TRAb (0.00 - 1.75 IU/L)

129.15 ± 165.95

0.38 ± 0.20

11.16 ± 10.82

15.519

14.190

14.858

TPOAb (0.00 - 34.00 IU/mL)

243.96 ± 273.46

13.32 ± 6.30

227.71 ± 208.57

16.715

0.942

8.107

TgAb (0.00 - 115.00 IU/mL)

499.20 ± 1091.53

20.96 ± 44.62

658.01 ± 1,172.04

8.679

-1.974

-2.701

**Table 2.** Univariate and Multivariate Logistic Regression Analysis of 19 Factors Among PTM Patients, GD W/O PTM Patients and Normal Persons (N = 1,200)
Independent variables	Univariate	Multivariate
Factors adjusted for in the multivariate analysis: sex, occupation, cigarette smoking, alcohol drinking, local trauma, venous stasis posture, AITD history/AITD, exophthalmos, acropachy, I-131 treatment and TRAb. OR: odds ratio; CI: confidence interval; PTM: pretibial myxedema; GD: Graves’ disease; GD w/o PTM: GD without PTM; AITD: autoimmune thyroid disease; TSH: thyroid-stimulating hormone; TT3: total T3; FT3: free T3; TT4: total T4; FT4: free T4; TRAb: TSH receptor autoantibody; TPOAb: thyroid peroxidase autoantibody; TgAb: thyroglobulin autoantibody.
Sex (male vs. female)	0.543 (0.426 - 0.692)	< 0.001	0.074 (0.038 - 0.144)	< 0.001
Age	1.023 (1.016 - 1.031)	< 0.001	1.048 (1.030 - 1.066)	< 0.001
Occupation	0.978 (0.876 - 1.092)	0.694
Cigarette smoking	1.622 (1.254 - 2.097)	< 0.001	4.481 (2.271 - 8.843)	< 0.001
Alcohol drinking	0.936 (1.311 - 2.197)	0.608
Local trauma	5.278 (3.603 - 7.732)	< 0.001	6.552 (3.135 - 13.691)	< 0.001
Venous stasis posture	4.843 (3.728 - 6.292)	< 0.001	6.161 (3.711 - 10.228)	< 0.001
AITD history/AITD	76.665 (31.393 - 187.227)	< 0.001	10.304 (2.370 - 44.800)	0.002
Exophthalmos	6.068 (4.655 - 7.911)	< 0.001	1.332 (0.820 - 2.163)	0.247
Acropachy	3.427 (2.223 - 5.284)	< 0.001	0.751 (0.346 - 1.630)	0.469
I-131 treatment	4.652 (3.596 - 6.017)	< 0.001	1.031 (0.641 - 1.658)	0.900
TRAb	52.846 (32.584 - 85.707)	< 0.001	42.928 (23.757 - 77.568)	< 0.001
TgAb	1.000 (1.000 - 1.000)	0.008	1.000 (1.000 - 1.000)	0.334
TPOAb	1.002 (1.002 - 1.003)	< 0.001	1.000 (0.999 - 1.001)	0.980
FT3	1.006 (0.980 - 1.033)	0.654
FT4	1.004 (0.996 - 1.013)	0.331
TT3	1.019 (0.945 - 1.100)	0.619
TT4	1.002 (0.999 - 1.004)	0.149
TSH	1.012 (1.006 - 1.018)	< 0.001	1.008 (1.000 - 1.017)	0.065

Table 2. Univariate and Multivariate Logistic Regression Analysis of 19 Factors Among PTM Patients, GD W/O PTM Patients and Normal Persons (N = 1,200)

Independent variables

Univariate

Multivariate

OR (95% CI)

P value

OR (95% CI)

P value

Factors adjusted for in the multivariate analysis: sex, occupation, cigarette smoking, alcohol drinking, local trauma, venous stasis posture, AITD history/AITD, exophthalmos, acropachy, I-131 treatment and TRAb. OR: odds ratio; CI: confidence interval; PTM: pretibial myxedema; GD: Graves’ disease; GD w/o PTM: GD without PTM; AITD: autoimmune thyroid disease; TSH: thyroid-stimulating hormone; TT3: total T3; FT3: free T3; TT4: total T4; FT4: free T4; TRAb: TSH receptor autoantibody; TPOAb: thyroid peroxidase autoantibody; TgAb: thyroglobulin autoantibody.

Sex (male vs. female)

0.543 (0.426 - 0.692)

< 0.001

0.074 (0.038 - 0.144)

< 0.001

Age

1.023 (1.016 - 1.031)

< 0.001

1.048 (1.030 - 1.066)

< 0.001

Occupation

0.978 (0.876 - 1.092)

0.694

Cigarette smoking

1.622 (1.254 - 2.097)

< 0.001

4.481 (2.271 - 8.843)

< 0.001

Alcohol drinking

0.936 (1.311 - 2.197)

0.608

Local trauma

5.278 (3.603 - 7.732)

< 0.001

6.552 (3.135 - 13.691)

< 0.001

Venous stasis posture

4.843 (3.728 - 6.292)

< 0.001

6.161 (3.711 - 10.228)

< 0.001

AITD history/AITD

76.665 (31.393 - 187.227)

< 0.001

10.304 (2.370 - 44.800)

0.002

Exophthalmos

6.068 (4.655 - 7.911)

< 0.001

1.332 (0.820 - 2.163)

0.247

Acropachy

3.427 (2.223 - 5.284)

< 0.001

0.751 (0.346 - 1.630)

0.469

I-131 treatment

4.652 (3.596 - 6.017)

< 0.001

1.031 (0.641 - 1.658)

0.900

TRAb

52.846 (32.584 - 85.707)

< 0.001

42.928 (23.757 - 77.568)

< 0.001

TgAb

1.000 (1.000 - 1.000)

0.008

1.000 (1.000 - 1.000)

0.334

TPOAb

1.002 (1.002 - 1.003)

< 0.001

1.000 (0.999 - 1.001)

0.980

FT3

1.006 (0.980 - 1.033)

0.654

FT4

1.004 (0.996 - 1.013)

0.331

TT3

1.019 (0.945 - 1.100)

0.619

TT4

1.002 (0.999 - 1.004)

0.149

TSH

1.012 (1.006 - 1.018)

< 0.001

1.008 (1.000 - 1.017)

0.065

**Table 3.** Comparison of Local Factors Precipitating PTM Relapse in Different Serum TRAb Levels
TRAb levels	Relapse (N)	Non-relapse (N)	Total (N)	RR	95% CI	P value
RR: relative risk or risk ratio or rate ratio; RR > 1: positive association between exposure factors and PTM relapse; RR = 1.0 - 1.1, no association between exposure factors and PTM relapse; RR = 1.2 - 1.4, the association is weak; RR = 1.5 - 2.9, the association is moderate; RR = 3.0 - 9.0, the association is strong; RR ≥ 10, the association is very strong. PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.
Elevated serum TRAb levels	164	153	317	6.73	1.65 - 100.10	0.003
Exposure
Trauma	19	4	23	8.81	12.79 - 164.83	< 0.001
Posture	78	50	128	6.5	6.96 - 32.66	< 0.001
Trauma + posture	58	12	70	8.84	18.51 - 117.94	< 0.001
Non-exposure	9	87	96	-	-	-
Normal serum TRAb levels	1	12	13	-	-
Exposure
Trauma	0	3	3	-	-	-
Posture	0	5	5	-	-	-
Trauma + posture	1	3	4	-	-	-
Non-exposure	0	1	1	-	-	-

Table 3. Comparison of Local Factors Precipitating PTM Relapse in Different Serum TRAb Levels

TRAb levels

Relapse (N)

Non-relapse (N)

Total (N)

95% CI

P value

RR: relative risk or risk ratio or rate ratio; RR > 1: positive association between exposure factors and PTM relapse; RR = 1.0 - 1.1, no association between exposure factors and PTM relapse; RR = 1.2 - 1.4, the association is weak; RR = 1.5 - 2.9, the association is moderate; RR = 3.0 - 9.0, the association is strong; RR ≥ 10, the association is very strong. PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.

Elevated serum TRAb levels

164

153

317

6.73

1.65 - 100.10

0.003

Exposure

Trauma

8.81

12.79 - 164.83

< 0.001

Posture

128

6.5

6.96 - 32.66

< 0.001

Trauma + posture

8.84

18.51 - 117.94

< 0.001

Non-exposure

Normal serum TRAb levels

Exposure

Trauma

Posture

Trauma + posture

Non-exposure